The overall objective of this integrated group of research studies is a more comprehensive understanding of the pathophysiology of manic-depressive disorders, particularly with regard to the complex interrelationships among clinical phenomenology, diagnosis, biological variables, and pharmacologic response. The studies are longitudinal; drug trials are double-blind. Major projects involve: (1) evaluation of tricyclic antidepressants that show specificity for a given monoamine neurotransmitter; (2) the study of phase shifts in sleep in cycling patients; (3) manipulation of sleep as a possible treatment of depression; (4) clinical and biochemical evaluation of electroconvulsive shock (ECT) in patients who have failed to respond to extensive and rigorous medication trials; (5) use of biological predictors of drug response including AER, MHPG, CSF, amine metabolites, neuroendocrine parameters and melatonin in blood and urine.